Overview

The goal of the ADGC is to identify genetic variants associated with risk for AD. It has long been known that genetic factors play an important role in the development of AD. Familial aggregation studies show that first degree relatives of probands with AD are more likely to have or develop AD compared to relatives of controls. Twin studies show a higher concordance of AD among monozygotic compared to dizygotic twins, with heritability estimates of 60% to 80%.

There are four know AD genes: (1) Amyloid precursor protein gene (APP); (2) Presenilin 1 gene (PSEN1); (3) Presenilin 2 gene (PSEN2); (4) Apolipoprotein E gene (APOE). Mutations in APP, PSEN1, and PSEN2 cause autosomal dominant early-onset (mostly <65 years) AD and account for a small fraction (<1%) of all AD cases. APP, PSEN1 and PSEN2 probably account for most if not all autosomal dominant early-onset AD. APOE is a susceptibility gene for more common late-onset AD with the ε4 allele conferring risk and influencing onset-age in a dose-dependent manner. APOE genotypes influence age-of-onset in APP, PSEN1 and PSEN2 mutation cases. However, ~40% of late-onset cases do not have the APOE high-risk ε4 allele and the population attributable risk of AD due to APOE has been estimated to be as low as 10 to 15%. For late-onset AD, complex segregation analysis shows there are 4-6 additional unknown AD susceptibility genes that influence onset age. However, identifying additional genetic variants has proven difficult.

Linkage analysis has been used to attempt to identify additional late-onset AD genes. Genome scans of multiplex family collections have consistently identified linkage to chromosome 19 near APOE. In addition, regions of chromosomes 6, 9, 10, 12, 19 and 21, appear to be most promising for late-onset AD or related phenotypes. However, no gene responsible for these linkage signals, except APOE, has been convincingly identified. Likewise a large number of genes, nominated as candidates either based on pathogenic mechanisms or presence at linkage peaks, have been individually tested for association to AD. A summary of more than 1,000 late-onset AD association studies can be found at http://www.alzgene.org. Recent work on sortilin is promisingthough additional studies are needed. Despite these vast efforts, no gene other than APOE has emerged that is consistently associated with AD.

The difficulty in gene identification is possibly related to the fact that AD is a complex disease characterized by marked phenotypic heterogeneity. While AD neuropathology is often expressed as clinical AD, it can also be expressed as MCI, and is common in persons without obvious cognitive impairment. Further, other common neuropathologic indices, especially cerebrovascular disease and Lewy bodies can impair cognition, including episodic memory, the clinical hallmark of AD, and contribute to clinically diagnosed AD. Finally, several factors unrelated to disease neuropathology are now known to be associated with impaired episodic memory further contributing to the clinical AD phenotype. Like other complex diseases, it is likely that this heterogeneity has hampered the ability of investigators to identify genetic variants associated with the disease. Thus a combination of larger studies and novel approaches such as GWAS will be needed to accomplish this important task.